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LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients

Giuseppe Bombaci, Mayuresh Anant Sarangdhar, Nicola Andina, Aubry Bernard Maurice Tardivel, Eric Chi-Wang Yu, Gillian M. Mackie, Matthew Pugh, Vedat Burak Ozan, Yara Banz, Thibaud Spinetti, Cédric Hirzel, Esther Youd (+8 others)
2021

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Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1 mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in COVID-19. However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine rich repeat (LRR) protein Ribonuclease inhibitor (RNH1), which
more » ... hares homology with LRRs of NLRP proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases IL-1b production and caspase-1 activation for inflammasome stimuli. Mechanistically, RNH1 decreases pro-IL-1b expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are dependent on caspase-1, respectively show increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Furthermore, RNH1 protein levels are negatively correlated with inflammation and disease severity in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity
doi:10.48350/164501 fatcat:op63l3elsre2zbirjqz7jhy4be
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Citation

Giuseppe Bombaci, Mayuresh Anant Sarangdhar, Nicola Andina, Aubry Bernard Maurice Tardivel, Eric Chi-Wang Yu, Gillian M. Mackie, Matthew Pugh, Vedat Burak Ozan, Yara Banz, Thibaud Spinetti, Cédric Hirzel, Esther Youd, Joerg C. Schefold, Graham Taylor, Amiq Gazdhar, Nicolas Bonadies, Anne Angelillo-Scherrer, Pascal Schneider, Kendle M. Maslowski, Ramanjaneyulu Allam. "LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients." (2021)